Pharmacokinetic/pharmacodynamic modeling/simulation and novel gastric retention formulation Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/3r074x68h

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  • This dissertation describes formulation of a gastric retention device (GRD) and sustained release (SR) hydrochlorothiazide beads at Oregon State University. Formulation condition and amounts of excipients had significant influence on characteristic of the GRD. The GRD containing SR hydrochlorothiazide beads was employed to assess bioavailability/bioequivalency study in healthy subjects. An original GRD was retained in the stomach with food and completed the drug release. However, this original GRD failed to stay on an empty stomach, leading to lower bioavailability than an immediate release (IR) tablet due to insufficient rigidity. The original device was modified to be more rigid, and this more rigid device successfully stayed on an empty stomach and achieved completion of the drug release at a slow release rate, the bioavailability and the drug effect on diuresis increased compared to the drug in an IR tablet. Less amount of hydrochlorothiazide at a slow release rate achieved equivalent diuresis to higher amount of the drug at a rapid release rate, which indicated slow drug release resulted in higher efficiency of hydrochlorothiazide. In vivo/in vitro correlation of hydrochlorothiazide in a modified GRD and an IR tablet was established to predict in vivo profile with in vitro dissolution profile prior to a clinical study. Pharmacokinetic/pharmacodynamic of nicotine was reviewed in terms of a relationship between plasma nicotine concentrations and pharmacological changes including heart rate and craving. Considering craving and development of tolerance to nicotine effect on cardio-acceleration, a dosing regimen with a combination of rapid input and constant slow input was suggested to improve smoking cessation. A simulation study was carried out to verify the current regulatory policy on assessing bioequivalency of enantiomeric drugs. First-order dissolution and absorption process, and nonlinear stereo-specific pre-systemic and systemic metabolism was taken into account to establish a pharmacokinetic model for the simulation. Four different dissolution profiles, within- and between-subject variability, dose and sample size were considered to simulate 1000 cross-over bioequivalency trials under standard bioequivalency criteria. Probability of false positives was determined to evaluate the current policy. The simulation study validated the importance of individual enantiomer pharmacokinetic for assessing bioequivalency study of the chiral drugs.
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